Traditional biodegradable polymers, like polyl(actic acid) (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA), see FIG. 1, do not have functionalities on their backbones. Such biodegradable polymer systems are therefore not able to covalently attach drugs or other therapeutic molecules for making drug delivery devices, or other functional molecules for a variety of applications. Instead, the functional molecules, such as therapeutic agents have to be physically entrapped into these polymers, either by forming micelles of by nano-encapsulation.
Recently, much attention has focused on the development of degradable and bioabsorbable polymers for biomaterials, and disposable or non-recoverable polymer goods applications. Biodegradable plastics are able to replace non-biodegradable polymers like polystyrene and poly(ethylene terephthalate) (PET) in a variety of applications. For example, Cargill Dow LLC under the trade name Nature Works is using PLA to make biodegradable products like dairy containers, food trays, cold drink cups, products for packaging applications, bottles for fruit juices, sport drinks and jams and jellies; poly(butylene succinate) is being used in agricultural applications in the form of mulch films, bags for seedlings and replanting pots; poly(butylene succinate) is also being used for manufacturing packaging films, bags and flushable feminine hygiene products because of its excellent mechanical properties. Traditional biodegradable polymers have included polyamides, polyanhydrides, polycarbonates, polyesters, polyesteramides, and polyurethanes, which incorporate a degradable linkage into the backbone that can be cleaved by hydrolytic, enzymatic and oxidative processes. Of these, aliphatic polyesters, specifically poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(ϵ-caprolactone) (PCL), have become the most widespread biomedical soft materials, finding use in drug and gene delivery, sutures, stents, dental implants and as tissue engineering scaffolding. Aliphatic polyesters have found success due to their ease of preparation, good mechanical properties and relatively quick in vivo degradation to small molecules easily absorbed or excreted by the body. However, PLA, PLGA and PCL lack pendant functional groups, which is a major limitation for a large number of applications. Pendant functionality is highly desirable for the fine-tuning of properties such as rate of crystallization, fire retardancy, color, hydrophobicity, bioadhesion, biodegradabiilty and the loading of therapeutics. Because of this, it is of great importance that an efficient route to main-chain functionalization of aliphatic polyesters and their random, graft, or block copolymers be found.
Polyesters are generally prepared by polycondensation of diols with diacids (A-A monomers+B-B monomers), self-condensation of hydroxyacids (A-B monomers), or by ring-opening polymerization of lactones. However, many useful functional groups, e.g. hydroxyl, thiol, amine and carboxylic acid, are incompatible with these types of polymerization as they form cross-links, eliminating the functionality. Protecting group chemistry, chemoselective step-growth polymerization and ring-opening polymerization of monomers with nonreactive functional groups have all been used to address this problem to varying degrees of success to prepare polyesters with hydroxyl, thiol, ketone, halogen, azido, alkyne and poly(ethylene glycol) (PEG) pendant groups. However, no highly versatile and general strategy for functionalization aliphatic polyesters has yet been developed.
2-Halo-3-hydroxypropionic acid (HHPA) is a halogenated constitutional isomer (C3H5XO3) of LA (C3H6O3), with a primary alcohol like GA (C2H4O3), and is therefore an ideal co-monomer for incorporation of α-halo ester functionality into PLGA, PLA, PGA and/or their copolymers with other classes of polymers, including both condensation and addition polymers. Such polyesters are potentially biodegradable, and can be further functionalized post-polymerization, via nucleophilic substitution, radical addition, radical-radical coupling and/or electrophilic substitution.
α-Halo esters are activated to nucleophilic attack by three mechanisms: inductive electron withdrawal by the adjacent carbonyl, reduced steric bulk at the σ* orbital of the carbon-halogen bond due to the adjacent carbonyl and through-space electron donation from the σ-orbital of the carbon-halogen bond to the π* orbital of the carbonyl. Because of this activation, α-halo esters undergo nucleophilic substitution by a number of hard (e.g. alcohol, alkoxide, carboxylate and primary amine), soft (e.g. cyanide, iodide, thio and thioalkoxide) and borderline hard/soft nucleophiles (e.g. azide, nitroxide and pyridine) under mild conditions. The major hurdle to this type of reaction is chain scission due to attack at the carbonyl or α-elimination. For these reasons, very reactive/hard nucleophiles such as alkoxide or carbanions may not be suitable for this type of reaction.
α-Halo esters participate in electrophilic substitution reactions via lithium metalation, Grignard and Reformatsky chemistries. Of these, Reformatsky reactions are the most mild and therefore, potentially of the most useful. The classical Reformatsky reaction involves the coupling of an α-haloester with an electrophile, via a zinc enolate intermediate. First, zinc reacts with an α-haloester, by insertion into the carbon-halogen bond, to form an enolate. This enolate is then reacted with an electrophile, traditionally an aldehyde or ketone but also an anhydride, phosphonate or α,β-unsaturated carbonyl.
α-Halo esters participate in radical reactions due to the weakness of the carbon-halogen bond, which undergoes homolytic cleavage under redox conditions to form a carbon centered radical. Curran et al. [Synthesis 1988, 489-513] and Matyjaszewski et. al. have shown that α-halo esters can add across the double bond of an olefin in atom transfer radical coupling and polymerization reactions, respectively. Depending on the structure of the olefin this can impart new functional groups onto the polymer, Jerome et. al. have used ring-opening of α-chloro lactones to prepare chloro functional polyesters. They further derivatized these polyesters by coupling with 3-butenyl benzoate to demonstrate radical coupling and using them as macroinitiators for the atom transfer radical polymerization (ATRP) of methacylate to prepare graft copolymers. Depending on the location of the α-halogen the architecture of the system can be controlled. If the halogen is spread throughout the polymer backbone, grafting-to or grafting-from structures can be made. If the halogen is at the chain end then block copolymers can be readily made.